Isoindol-1-one analogues of 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]pipera zine (p-MPPI) as 5-HT1A receptor ligands.
In developing radioiodinated antagonists for in vivo imaging of 5-HT1A receptors with SPECT, a series of new arylpiperazine benzamido derivatives, including 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridyl)-p-iodobenzamido]ethyl]p iperazine (p-MPPI, 31) (Kd = 0.36 nM), as potential ligands for 5-HT1A receptors were reported previously. However, rapid in vivo metabolism may have caused the breakdown of the amide bond of [123I]-31 and rendered this agent obsolete as an in vivo imaging agent in humans. To improve the in vivo stability of 31, a series of cyclized amide analogues were designed and synthesized. In vitro binding, metabolic stability, and in vivo biodistribution of these new derivatives were investigated. Several five-membered-ring isoindol-1-ones displayed very high in vitro binding affinity, especially 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-6-nitro-3-phenyl-2, 3-dihydroisoindol-1-one, 15, 3-hydroxy-6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}- 3- phenyl-2,3-dihydroisoindol-1-one, 18, and 6-iodo-2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-3-phenyl-2, 3-dihydroisoindol-1-one, 21, which showed Ki values of 0.05, 0.65, and 0.07 nM, respectively. The affinities for 5-HT1A receptors of other cyclized amide derivatives, 5-(4-bromophenyl)-1-{2-[4-(2-methoxyphenyl)- piperazin-1-yl]ethyl}pyrrolidin-2-one, 25, 5-(4-iodophenyl)-1-{2-[4-(2-methoxyphenyl)piperazin- 1-yl]ethyl}pyrrolidin-2-one, 27, and 2-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-2,3-dihydro- isoindol-1-one, 29, were 1.09, 2.54, and 14.9 nM, respectively. Compared to [125I]-31, iodinated cyclized amide derivatives [125I]-21 and [125I]-27 displayed a slower metabolism in human liver microsomal and cytosolic preparations. Biodistribution of [125I]-21 and [125I]-27 in rats (after an i.v. injection) displayed moderate to low brain uptakes with little or no specific localization in hippocampal region, where 5-HT1A receptors are concentrated. These data indicate that the new iodinated ligands showed high binding affinities and better metabolic stability but displayed unexpectedly low selective binding to 5-HT1A receptors in vivo. Additional structural modifications may be needed to correct the unfavorable properties displayed for these iodinated cyclized amide derivatives for in vivo biodistribution in rats.
Zhuang
Z P
ZP
Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
Kung
M P
MP
Mu
M
M
Kung
H F
HF
D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism*; D054833:Isoindoles; D007700:Kinetics; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
D000631:Aminopyridines; D006571:Heterocyclic Compounds; D007211:Indoles; D007457:Iodine Radioisotopes; C110621:Isoindol-1-one; D054833:Isoindoles; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C087205:4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine